title: Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt.
abstract: Forkhead box O (FOXO) transcription factors, the key regulators of cell survival, are negatively controlled through the PI3K-Akt signaling pathway. Phosphorylation of FOXO by Akt leads to cytoplasmic localization and subsequent degradation via the ubiquitin-proteasome system. Here we show a paradigm of FOXO1 regulation by the protein arginine methyltransferase PRMT1. PRMT1 methylated FOXO1 at conserved Arg248 and Arg250 within a consensus motif for Akt phosphorylation; this methylation directly blocked Akt-mediated phosphorylation of FOXO1 at Ser253 in vitro and in vivo. Silencing of PRMT1 by small interfering RNA enhanced nuclear exclusion, polyubiquitination, and proteasomal degradation of FOXO1. PRMT1 knockdown led to a decrease in oxidative-stress-induced apoptosis depending on the PI3K-Akt signaling pathway. Furthermore, stable expression of enzymatic inactive PRMT1 mutant increased resistance to apoptosis, whereas this effect was reversed by expression of phosphorylation-deficient FOXO1. Our findings predict a role for arginine methylation as an inhibitory modification against Akt-mediated phosphorylation.
authors.affiliation: Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yamagata
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Daitoku
authors.forename: Yuta
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Kana
authors.initials: K
authors.lastname: Namiki
authors.forename: Koji
authors.initials: K
authors.lastname: Hisatake
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kako
authors.forename: Hidehito
authors.initials: H
authors.lastname: Mukai
authors.forename: Yoshitoshi
authors.initials: Y
authors.lastname: Kasuya
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D017209:Apoptosis; D001120:Arginine / Q000378:metabolism*; D016384:Consensus Sequence; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D008745:Methylation; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D012694:Serine / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology; D054875:Ubiquitination
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins; D012694:Serine; D001120:Arginine; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex